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Medullary neurostimulation in refractory angina
Techniques in Regional Anesthesia and Pain Management (2006) 10, 16-23
Medullary neurostimulation in refractory angina X. Garcia-Moll, MD, R. Serra, MD From the Department of Cardiology and Anaesthesiology, Recovery and Pain Treatment, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain. KEYWORDS: Refractory angina; Ischemic heart disease; Spinal cord stimulation; Chronic pain
A growing number of patients present a clinical picture of refractory angina despite major advances in the pharmacological treatment of angina pectoris and myocardial reperfusion techniques. According to the European Society of Cardiology guidelines, refractory angina is a chronic pathology characterized by myocardial ischemia due to coronary artery disease that cannot be controlled by a combination of maximum tolerated drug treatment, angioplasty, and coronary revascularization surgery. To determine that a patient is not a candidate for revascularization, it has to be ruled out on the basis of a recent coronary angiogram, and the patient must be receiving the maximum tolerated doses of medical treatment. There must also be proof of reversible ischemia, and other non-coronary causes of chest pain must be ruled out. If all of the above does not resolve, then angina transcutaneous electrical nerve stimulation (TENS) or medullary electricostimulation (MES) should be considered. There are basically two mechanisms responsible for this clinical improvement: modification (not eradication) of pain perception, and its anti-ischemic properties in the myocardium. In this review, we describe our experience and we discuss the long-term symptomatic improvement and lower the functional category obtained with TENS or MES in patients with refractory angina. © 2006 Elsevier Inc. All rights reserved.
The past 15 years have seen major advances in the pharmacological treatment of angina pectoris and myocardial reperfusion techniques (angioplasty and surgery). Nonetheless, a growing number of patients present a clinical picture of refractory angina. According to the European Society of Cardiology guidelines, refractory angina is a chronic pathology characterized by myocardial ischemia due to coronary artery disease that cannot be controlled by a combination of maximum tolerated drug treatment, angioplasty, and coronary revascularization surgery. To confirm the diagnosis, it is necessary to demonstrate that reversible myocardial ischemia is the cause of the symptoms. Duration of more than 3 months is defined as chronic.1 To determine that a patient is not a candidate for revascularization, clinical cardiologists, interventional cardiologists, and heart surgeons must rule out the possibility of revascularization on the basis of a recent coronary angiogram, and the patient must be receiving the maximum tolerated doses of medical treatment. There must also be proof of reversible ischemia, and other noncoronary causes of Address reprint requests and correspondence: R. Serra, MD, Department of Anaesthesiology, Recovery and Pain Treatment, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain. E-mail address: [email protected]. 1084-208X/$ -see front matter © 2006 Elsevier Inc. All rights reserved. doi:10.1053/j.trap.2006.02.005
chest pain must be ruled out. Finally, information on the patient’s psychosocial situation is essential, as this may be an important cause of symptoms. There are no reliable data on the prevalence or incidence of refractory angina. The only data available are those extrapolated from coronary angiography records (5-15% of coronary angiography results are considered nonrevascularizable), or taken from data on chronic angina. About 5% to 10% of patients with unstable angina have a myocardial infarction or refractory angina in the hospital,2 and it is therefore likely that the number of patients with refractory angina will rise. A Spanish review of stable angina showed a prevalence of approximately 7.5% in people between the ages of 45 and 74,3 and it is thought that the figures are higher in northern Europe. In summary, we can say that the incidence in absolute numbers is 30,000 to 50,000 patients per year in Europe.
Determining suitable medical treatment for refractory angina The first step is to study the patient’s medical treatment because it is common that not all patients referred for
Garcia-Moll and Serra Table 1
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Diagnosis
I. Requires assessment by cardiologists and heart surgeons to ensure that the symptoms are of ischemic origin and that revascularisation is not possible. It is advisable to perform coronary angiography to exclude any new lesions that may call for intervention. II. Determine the presence of reversible myocardial ischemia when the decision is taken. III. The outpatient visit should include a review of pain history, physical examination and analysis of the patient’s medical treatment. We must ensure that the patient does not respond to the maximum tolerable treatment. We must also bear in mind the possibility of poor compliance with therapy, and explain the importance of complying fully with the treatment. IV. Exclude non-cardiac causes such as costochondritis, intercostal neuralgia, anaemia, thyrotoxicosis, reflux esophagitis. V. Multidisciplinary pain management, which can be based on psychological assessment methods such as hospital anxiety and depression scores. It should be determined whether psychotherapy may be beneficial since anxiety and depression are usually major pain components. The HADS questionnaire (Hospital Anxiety and Depression Score) is a simple screening tool to help identify patients who can benefit from a psychiatric or psychological study. VI. Rehabilitation program including secondary prevention by actively managing risk factors, physical reactivation, stress management and psychological support.
refractory angina are truly refractory to treatment. It is possible to increase the dose or try new drug combinations, and more aggressive treatment can improve symptoms in 45% to 83% of patients.4,5 Our diagnosis and treatment algorithm is described in Table 1, and is an adaptation of the algorithm recommended by the European Society of Cardiology.6,7 All patients should undergo antiaggregation and/or anticoagulation treatment in the absence of contraindications. Beta-blocker doses should be increased until a basal heart rate between 55 and 60 beats per minute is reached. The combination of beta-blockers with long-half-life calcium antagonists may provide significant improvement. The time of drug administration is also relevant. Patients with predominantly nocturnal angina should receive more medication at that time of day, whereas patients with exertion angina should get them in the morning. Given the circadian predominance of early-morning pain, we should consider administering topical nitroglycerin at night to cover the early morning hours. Nitrates may be limited because of tolerance. Other options may include molsidomine or nicorandil instead of nitrites during the period without topical nitrates. Amiodarone also has antiangina properties, although the evidence is limited. Obviously, aggravating factors like anemia, atrial fibrillation with rapid ventricular response, hypertension, or thyroid dysfunction must be corrected. We must not overlook the aggressive management of high cholesterol levels, which may provide long-term ben-
17 efits. The reduction of LDL cholesterol improves endothelial function in conductance vessels. An aspect of treatment that is often overlooked is cardiac rehabilitation. The functional limitation caused by refractory angina is usually considerable and may hamper patients so they cannot perform normal daily activities, causing them to feel socially isolated and incapable of physical activity, as they become increasingly dependent on their milieu. Although there are no guidelines on cardiac rehabilitation for patients with refractory angina, it is advisable to set up a rehabilitation program with these patients to reactivate them physically,8-12 help them stop smoking, lose excess weight, and change sedentary habits. Physical activity and a physically active life reduce cardiac mortality,13 prevent the development of atherosclerotic plaque,14 and improve myocardial perfusion.15 The program should be tailored to each patient’s needs. The patient should be informed about the use of prophylactic nitroglycerin before physical exercise and understand the importance of warm-up and cooling-off periods before and after exercise. If all of the above does not resolve the angina, other therapeutic options should be considered, such as transcutaneous electrical nerve stimulation (TENS) or medullary electrostimulation (MES). Opioids can be used in cases of refractory angina when other treatments fail. It is important to follow the opioid treatment guidelines for nonmalignant chronic pain and select patients adequately since the risk of addiction is low in socially well-adapted people with no history of drug abuse. Refractory angina is a pathology that seriously affects the quality of life and will probably increase in magnitude. Fortunately, we now have alternative treatments available, one of which is medullary electrostimulation (MES).
Medullary electrostimulation Electrical stimulation via electrodes as a treatment for intractable chronic pain began in 1967.16 Since then, MES has been used for many types of pain: tumors, lesions of the brachial plexus, phantom limb pain, angina pectoris, multiple sclerosis, peripheral vascular disease, arachnoiditis, etc. Early in the 1980s, Mannheimer and coworkers began treating angina pain with transcutaneous electrical nerve stimulation (TENS), and in 1987, Murphy and coworkers published the first results on the use of MES.17,18 Today its beneficial effect on the quality of life,19-21 by cutting down on angina episodes and enhancing functional capacity,22,23 has been amply demonstrated. There are basically two mechanisms responsible for this clinical improvement: modification (not eradication) of pain perception (the stimulation of spinal cord fibers that do not transmit pain to the brain lessens the impulses from fibers that do transmit it),24 and its antiischemic properties in the myocardium,25-31 although its mechanism of action is still a subject of controversy. The mechanisms suggested are a direct antiischemic effect due to diminished oxygen consumption in the myocardium or a redistribution of coronary
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Table 2 Clinical characteristics of the 56 patients included in our series Males (n, %) Age (years) Duration of ischemic heart disease (years) Duration of angina (years) NYHA class Previous acute MI (n, %) Previous PTCA (n, %) Previous revascularization surgery (n, %) Number of vessels involved Patients with three vessels (n, %) LVEF (%) Patients with 40% LVEF (n, %) Number of angina episodes per week Number of NTG per week
41, 73.2% 65.0 ⫾ 8.1 10.4 ⫾ 5.4 8.5 ⫾ 5.1 3.7 ⫾ 0.5 43, 76.3% 19, 33.9% 42, 75% 2.8 ⫾ 0.6 42, 75% 47.7 ⫾ 16.2 22, 39% 7.7 ⫾ 3.4 6.6 ⫾ 3.8
flow.17,31-34 This effect could be explained by the reduction of sympathetic tone or by a change in the cardiac metabolism of beta-endorphin.35-37 The antiischemic effect has been demonstrated in studies with 24-hour Holter ambulatory ECG recordings and exercise tests in which it has been shown that depression of the ST segment, indicative of the presence of myocardial ischemia, is reduced under medullary stimulation.19,22,23 Furthermore, the onset of angina is delayed.32 However, there is controversy over whether myocardial perfusion is increased during maximum exercise. Some studies show that myocardial perfusion improves in ischemic areas, with concomitant alteration of the coronary flow reserve as assessed by positron emission tomography.38 The difference in results could be explained by the different experimental methods. There is currently no doubt that MES does not have an anesthetic effect, which means that the patient will feel pain with a major angina episode or a myocardial infarction.39 This is one of the main reasons for reticence within the cardiology community: the safety of MES. It is felt that if the reduced angina is due exclusively to an anesthetic effect on pain sensitivity, the patient will continue to experience the same ischemic episodes, completely silent because of the electrostimulation, with the consequent danger resulting from eliminating the alarm signal, which is the angina pain. However, it has been shown that patients retain the ability to feel ischemic pain.
Medullary electrostimulation: our experience Our series consisted of 56 patients (from 1 February 1993 to 31 August 2005) treated for refractory angina with MES. Their clinical profiles are shown in Table 2. All of them met the following inclusion criteria: (a) severe exertion angina (class III-IV) or subacute unstable angina, released from the coronary care unit but with continued episodes preventing their release from hospital; (b) angina resistant to maximum tolerated drug treatment, despite good compliance, over a period of at least 1 month; (c) severe lesions (⬎70%) in the coronary arteries, demonstrated by coronary angiography; (d) reversible myocardial ischemia documented by challenge testing or ECG record-
ing during a pain episode; (e) technical impossibility of myocardial reperfusion (surgery or coronary angioplasty [PTCA]) or very high-risk surgical indication; (f) reasonable certainty that pain episodes were mainly of ischemic origin (chest pain episodes described by the patient as identical to those felt in our presence with electrocardiographic changes, which remitted or improved with sublingual nitroglycerin [s.l. NTG]); (g) absence of correctible aggravating factors; and (h) informed consent.
Implantation of electrostimulator, possible complications, and follow-up Before performing the procedure, we checked compliance with the inclusion criteria and suspended the administration of antiaggregants 10 days before implantation. If the patient was under treatment with dicumarinics, we switched to heparin beforehand. One hour before the procedure we administered an antibiotic (cefazolin). The entire system was implanted in a single operation in two stages. In the first stage of the procedure, we placed the electrode under fluoroscopic control with the patient in prone decubitus (Figure 1). We found it useful to place a few paper clips in the skin to locate the area where we wanted to insert the electrode tip and to ensure that the patient was in an anteroposterior position (Figure 2). Once the patient was positioned and with maximum sterility guaranteed, we started the procedure under local anesthesia at T4 –T5 to locate the epidural space and insert the electrode percutaneously. Under fluoroscopic control, it was placed in the C7–T2 epidural space so that it would cause paresthesia in the region where the angina pain irradiated. With the electrode in place, we tunnelled through the rest of the right side and closed the skin provisionally (Figure 3). With this maneuver we could ensure that there were no kinks in the electrode, keep the extension wire area as small as possible, and minimize patient discomfort. We then went to a second surgical stage with the patient in lateral decubitus to place the extension wire and the impulse generator in a subcutaneous pouch, usually in the right subcostal area (in right-handed patients), making it easier for the patient to operate the controls. The complications related to MES may be technical or biological.40 The technical complications most often reported in the literature are breakage or displacement of the electrodes, depleted batteries, or generator failure.41,42 Migration of the electrode has been described in 23% of cases,43 especially with unipolar electrodes (up to 45%). In our experience, this percentage was considerably lower— around 10%. The biological complications most often described are infection of the system (2% in our experience), loss of cerebrospinal fluid, pain at the site of the incision, electrode or generator,41 epidural bleeding, seroma, hematoma, paralysis, over- or under-stimulation, allergic reaction, etc. Clinical controls were performed by the clinical cardiologist and the implanting anesthesiologist 1 month after implantation of the system and every 4 to 6 months thereafter (depending on the patient’s stability). The following items were monitored during follow-up: weekly sublingual
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Figure 1
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First stage of system implantation. Prone decubitus. (Color version of figure appears online.)
NTG consumption, number of weekly angina episodes, death from cardiac causes, death from noncardiac causes, cardiovascular clinical events requiring hospitalization (acute myocardial infarction [acute MI], unstable angina, heart failure, stroke), and complications inherent in the procedure itself (displacement or breakage of the electrodes, infection, extrusion of the battery, etc.).
The patients were also assessed with the Nottingham Health Profile44 before the procedure, 1 month after, and thereafter every year. This test includes seven parameters: physical mobility, sleep, energy, social isolation, emotional reactions, pain, and overall assessment.
Results of our experience
Figure 2
Final electrode position.
The European series, the largest published up to now (n ⫽ 517 patients),45 had a mean follow-up of 23 months (0-128) for the entire patient group, 23 months (0-128) for the survivors, and 19 months (0-122) for patients who died. The follow-up in our series was considerably longer: 49.0 ⫾ 34.6 months for the total, 61.0 ⫾ 38.4 months for survivors, and 36.1 ⫾ 25.1 months for those who died (P ⫽ 0.001). The causes of death in the European series were cardiac in 51%, noncardiac in 24%, and unknown in 25%, whereas in our group, they were 65%, 17%, and 17%, respectively. It was estimated that the mortality rate in the former group of patients was 3.5% to 5% per year, lower than that found in our series and probably due to the substantial difference in follow-up (in our experience the mortality rate was lower in the first few years and increased as the follow-up lengthened). The left ventricular ejection fraction was a relevant variable in patient prognosis. Patients with LVEF ⬍ 40% had a higher mortality rate than those with LVEF ⬎ 40%. The functional class improved significantly after MES implantation. The basal overall and pain scores recorded by the Nottingham profile improved significantly after the first month (basal pain: 62.0 [50.0-75.0]; pain at 1 month: 25.0 [12.041.0]; P ⬍ 0.001; basal overall: 71.0 [43.0-85.0]; overall at 1 month: 28.0 [14.0-57.0]; P ⬍ 0.001). The Nottingham profile administered at the end of 1 year did not show significant differences as compared with the scores 1 month
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Figure 3
Second stage of system implantation. Lateral decubitus. (Color version of figure appears online.)
after implantation, suggesting that the beneficial effect is sustained over time (pain: 25.5 [12.5-52.3]; overall: 33.0 [14.0-57.0]). During the follow-up, 23 patients (56.1%) had no cardiovascular complications that required hospitalization; the remaining 18 patients (43.9%) recorded a total of 29 admissions. The most common complication found during follow-up was unstable angina, followed by acute myocardial infarction, heart failure, and stroke. Twenty-four patients died (5 from fatal MI, 5 from heart failure, 2 of stroke, and 6 from sudden death—1 from cancer, 1 from pneumonia, and 4 of undetermined causes). Consequently, the overall yearly mortality rate was 9.7% and 7.7% for cardiac causes. The
Figure 4
only technical complications we recorded were a case of immediate postimplantation infection that required the removal of the entire implant and placement of a new system 3 months later, and a case of extrusion of the extension wire 6 months after implantation, which was resolved by removal and placement of a new wire which has now been functioning correctly for 45 months. Finally, we had a case of electrical cellulites at the level of the IPG-implantable generator pocket programmed in unipolar mode in a patient 5 years after treatment, which was resolved by switching to bipolar mode (Figure 4). We had no cases of electrode breakage or displacement. We took chest and cervical (AP and lateral) X-rays to ensure the correct position of the electrode in the posterior
Electrical cellulitis secondary to unipolar stimulation. (Color version of figure appears online.)
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epidural space. Patients followed a stimulation schedule of 1 hour every 8 hours.
Discussion MES systems have been implanted in approximately 2000 patients worldwide.46 The long-term follow-up studies show that symptoms improve in approximately 80% of patients.47 This improvement depends on appropriate patient selection and careful monitoring in care units specialized in this type of treatment. With MES there has been a significant reduction in the number of angina episodes and nitrate consumption, even in the long term, with improvement in functional class and significant reduction in the number of hospital admissions.27,28,39,43,47-50 In our experience, MES has drastically lowered the number of admissions per patient per year (2.3 as compared with 0.28).39 Hospital visits were twice higher in the group of deceased patients when compared with the group of living patients (0.37 as compared with 0.19). However, in the deceased group, the number of admissions was drastically reduced in relation to the pretreatment rate (2.03 as compared with 0.37). This reduction may contribute to improve quality of life while reducing health costs. The enhanced quality of life was also reflected in the significant improvement in the Nottingham profile indices in the short and long term within the population studied. In our series, cardiovascular events represented the main cause of mortality with 7.7% of the cases per year of the total 9.7% per year. These figures are similar to those in the only two studies, both retrospective, that have provided information to date on morbidity and mortality in patients treated with electrostimulation. The European retrospective multicenter study51 mentions only the overall mortality, which was 8% per year, and in the historical cohort study by De Jongste52 with 57 patients monitored for an average of 23 months, the mortality rate was 6.5%. A study with mortality figures in patient groups with a comparable profile but without MES treatment is the Coronary Artery Surgery Study (CASS)53-55 and the Framingham cohort.56,57 In this North American study, cardiac mortality in patients with three vessels involved was 32% over 4 years and increased to 50% in the subgroup with a left ventricular ejection fraction below 35%. Therefore, the mortality found in our series of patients treated with MES was not greater than expected in patients with a similar clinical profile, as shown in the ESBY study,58 which suggests that neuromodulation is as effective as coronary revascularization, in reducing anginal episodes and mortality. Other studies have provide additional data to rule out the concern that MES causes higher mortality.27,59,60
21 A retrospective study showed that MES has no negative influence on mortality or morbidity as compared with matched groups,45 which is similar to the findings in our prospective series as compared with data taken from the literature on patients with similar characteristics without MES treatment.39 Indeed, the ESBY study showed that patients who are candidates for revascularization surgery with higher surgical risk randomized to MES had less mortality (but a higher rate of readmissions for angina) than patients randomized to revascularization surgery.62 Both groups showed significantly fewer angina episodes and reduced sublingual nitroglycerin intake, with no difference between them. The effects were sustained at 5 years.63 In our series, we assessed the mortality-predicting parameters (yes/no) by logistic regression and identified the following independent variables associated with mortality: ejection fraction of 40% or less (in accordance with data currently available on the relevance of this parameter as a prognostic factor in ischemic heart disease) and sex. In our series, men had a lower mortality rate than women, even after adjusting for the ejection fraction and years of ischemic heart disease. A third parameter that tended to be associated with mortality was the previous duration of ischemic heart disease, probably because this variable encompasses others, such as the number of prior infarctions or prior revascularization. On the other hand, as opposed to the European series, diabetes and the absence of beta-blockers in treatment had no independent predictive value in our series. Another item worthy of mention is the low incidence of technical complications like electrode breakage or displacement. This is common to all the series published after tetrapolar electrodes came into use, doing away with the large number of problems found in earlier studies. An additional advantage of MES is that it is a treatment system that can be removed, as opposed to ablation surgery. Moreover, MES has no long-term side effects, as compared with the major systemic side effects of opioids. In our series, we looked specifically at the follow-up of unstable angina cases in the subacute stage, which is an indication that has been much discussed up to now. The mortality rate in this group of patients was higher but not statistically significant. Morbidity was similar and the improvement in quality of life was greater. This is not surprising since, if we compare the clinical profiles of both groups of patients, we note that they are very much alike. Actually, they are the same type of patients, with numerous hospital admissions at two different moments in their disease progression—some during the outpatient period after being released from hospital, and others while in hospital, following the acute phase in the coronary care unit. Finally, our data confirm the hypothesis that refractory unstable angina in the subacute phase is a valid indication for MES treatment.
Clinical efficacy studies TENS and MES have been shown to provide long-term symptomatic improvement and lower the functional category as established by the Canadian Cardiovascular Society, enhancing the possibilities for everyday social activities and reducing the intake of sublingual nitroglycerin.61
Conclusion MES is a valid technique safe in the long term for treating patients with refractory angina, since it reduces morbidity,
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does not increase mortality, and has a low incidence of technical complications. MES can therefore be considered a safe and effective therapeutic alternative for this type of patients, in both the stable and subacute unstable phases. Its lasting long-term beneficial effects can also have a positive impact on economic and social costs by cutting down on the number of patient days in hospital.
References 1. Mannheimer C, Camici P, Chester MR, Collins A, DeJongste M, Eliasson T, Follath F, Hellemans I, Herlitz J, Lüscher T, Pasic M, Thelle D: The problem of chronic refractory angina: Report from the ESC Joint Study Group on the Treatment of Refractory Angina. Eur Heart J 23(5):355-370, 2002 2. Yusuf S: Design, baseline characteristics, and preliminary clinical results of the Organization to Assess Strategies for Ischemic Syndromes-2 (OASIS-2) trial. Am J Cardiol 1999;84(5A):20M–25 3. Cosín J, Asín E, Marrugat J, et al: Prevalence of angina pectoris in Spain. PANES Study group. Eur J Epidemiol 4:323-330, 1999 4. Ruck A, Drvota V, KastrupJ, DudekD, Boetker HE, Ruzyllo W, Glogar D, Sylvén C: On behalf: the EUROINJECT ONE investigators. How refractory is refractory angina? A three-year follow up of 225 patients. Abstract 3853. European Society of Cardiology Congress 2005. Stockholm September 3rd-7th 2005 5. Nägele H, Kalmar P, Labeck M, et al: Transmyokardiale Laserrevaskularisation —Behandlungsoption bei der koronaren Herzerkrankung. Z Kardiol 86:171-178, 1997 6. Chester M: Draft guidelines for the management of refractory angina on behalf of the UK Refractory Angina Group. Eur Heart J 1999; 20(Abstr Suppl):479 7. Eliasson T: Therapeutic options in severe angina pectoris and endstage coronary artery disease. In: XXth Congress of the European Society of Cardiology; 1998 8. WHO: The rehabilitation of patients with cardiovascular diseases. Report on a seminar. EURO 0381. Copenhagen, 1969: WHO, regional office for Europe; 1969 9. Second Joint Task Force of European and other Societies on Coronary Prevention. Prevention of coronary heart disease in clinical practice. Eur Heart J 19:1434-1503, 1998 10. Working group on Rehabilitation of the European Society of Cardiology. Long-term comprehensive care of cardiac patients. Eur Heart J 1992;13 (Suppl C) 11. Smith S, Blair S, Crique M, et al: American Heart Association Consensus statement: Prevention of heart attack and death in patients with coronary artery disease. Circulation 92:2-4, 1995 12. Wenger N. Froelicher E. Smith L. el at: Clinical Practice Guideline: Cardiac Rehabilitation. U.S. Department of Health and Human Services. AHCPR publication 13. O’Connor G, Buring J, Yusuf S, et al: An overview of randomized trials of rehabilitation with exercise after myocardial infarction. Circulation 80:234-244, 1989 14. Niebauer J, Hambrecht R, Velich T, et al: Attenuated progression of coronary artery disease after 6 years of multifactorial risk intervention. Circulation 96:2534-2541, 1997 15. Linxue L, Nohara R, Makita S, et al: Effect of long-term exercise training on regional myocardial perfusion changes in patients with coronary artery disease. Jpn Circ J 63:73-78, 1999 16. Shealy S, Mortimer JT, Reswick JB: Electrical inhibition of pain by stimulation of the dorsal columns: preliminary clinical report. Anesth Analg 46:489-491, 1967 17. Mannheimer C, Carlson CA, Emanuelsson H, Vedin A, Vaagstein F, Wilhelmsson C: The effects of transcutaneous electrical nerve stimulation in patients with severe angina pectoris. Circulation 71:308-316, 1985 18. Murphy DF, Giles KE: Dorsal column stimulation for pain relief from intractable angina pectoris. Pain 28:365-368, 1987
19. De Jongste MJL, Hautvast RWM, Hillege JL, Lie KI on behalf of the Working Group on Neurocardiology. Efficacy of spinal cord stimulation as adjuvant therapy for intractable angina pectoris. J Am Coll Cardiol 23:1592-1597, 1994 20. García Moll M, García-Moll X, Serra R: Tratamiento de la angina refractaria con electroestimulación medular: impacto sobre la calidad de vida [resumen]. Rev Esp Cardiol 50(Supl 6):370, 1997 21. González-Darder JM, Vázquez JL, Canela P, González-Martínez V: Calidad de vida en el paciente con angina inestable tratado con estimulación eléctrica medular. Med Clin (Barc) 95:768-770, 1990 22. Sanderson JE, Brooksby P, Waterhouse D, Palmer RGB, Neubauer K: Epidural spinal electrical stimulation for severe angina: a study of its effect on symptoms, exercice tolerance and degree of ischemia. Eur Heart J 13:628-633, 1992 23. Mannheimer C, Augustinsson LE, Carlsson CA, Manhem K, Wilhelmsson C: Epidural spinal electrical stimulation in severe angina pectoris. Br Heart J 59:56-61, 1988 24. Melzack R, Wall PD: Pain mechanisms: a new theory. Science 150: 971-979, 1965 25. González-Darder JM, González-Martínez V, Canela P, Hernández R: Estimulación eléctrica medular en la angina rebelde e incapacitante. Protocolo y resultado a largo plazo. Neurocirugía 4:305-311, 1993 26. De Jongste MJL, Haaaksma J, Hautvast RWM, Hillege HL, Meyler JW, Staal MJ et al: Effects of spinal cord stimulation on myocardial ischemia during day life in patients with severe coronary artery disease. A prospective ambulatory electrocardiographic study. Br Heart J 71:413-418, 1994 27. Sanderson JE, Ibrahim B, Waterhouse D, Palmer RBG: Spinal electrical stimulation for intractable angina; long-term clinical outcome and safety. Eur Heart J 15:810-814, 1994 28. Elliasson T, Fern S, Augustinsson LE, Mannheimer C: Safety aspects of spinal cord stimulation in severe angina pectoris. Coron Artery Dis 5:845-850, 1994 29. Hautvast RWM: Spinal cord stimulation for chronic refractory angina pectoris; an investigation of its efficacy, mechanism and neuronal pathways [tesis doctoral]. Groningen, Holanda: University of Groningen, 127-139, 1997 30. Kujacic V, Eliasson T, Mannheimer C, Jablonskiene D, Augustinsson LE, Emanuelsson H: Assessment of the influence of spinal cord stimulation on left ventricular function in patients with severe angina pectoris: an echocardiographic study. Eur Heart J 14:1238-1244, 1993 31. Mannheimer C, Eliasson T, Andersson B, Bergh CH, Augustinsson LE, Emanuelsson H: Effects of spinal cord stimulation in angina pectoris induced by pacing and possible mechanisms of action. BMJ 307:477-480, 1993 32. De Landsherre C, Mannheimer C, Habets A, et al: Effect of spinal cord stimulation on regional myocardial perfusion assessed by positron emission tomugraphy. Am J Cardiol 69:1143-1149, 1992 33. Hautvast R, De Jongste M, Blanksma P, et al: Spinal cord stimulation causes redistribution in myocardial perfusion during dipramidole stresss testing in patients with refractory angina pectoris as assessed by 13 NH3-positron emission tomography. Am J Cardiol 77:462-467, 1996 34. Mobilia G, Zuin G, Zanco P, et al: Effects of spinal cord stimulation on regional myocardial blood flow in patients with refractory angina. A positron emission tomography study. (In italian). G Ital Cardiol 28:1113-1119, 1998 35. Norrsell H, Eliasson T, Mannheimer C, et al: Effects of pacinginduced myocardial stress and spinal cord stimulation on whole body and cardiac norepinephrine spillover. Eur Heart J 18:1890-1896, 1997 36. Emanuelsson H, Mannheimer C, Waagstein F, Wilhelmsson C: Catecholamine metabolism during pacing-induced angina pectoris and the effect of transcutaneous electrical nerve stimulation. Am Heart J 114: 1360-1366, 1987 37. Eliasson T, Mannheimer C, Waagstein F, et al: Myocardial turnover of endogenous opioids and calcitonin gene-related peptide in the human heart and the effects of spinal cord stimulation on pacing-induced angina pectoris. Cardiology 89:170-177, 1998 38. Hautvast RW, Blanksma PK, De Jongste MJ, Pruim J, van der Wall EE, Vaalburg W, Lie KI: Effect of spinal cord stimulation on myocardial blood flow assessed by positron emission tomography in patients with refractory angina pectoris. Am J Cardiol 77(7):462-467, 1996
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39. Garcia-Moll M, Serra R, Garcia-Moll X: Refractory angina treated by spinal cord stimulation. The results of a long-term follow-up. Rev Esp Cardiol 53(3):321-326, 2000 40. Cameron T: Safety and efficacy of spinal cord stimulation for the treatment of chronic pain: a 20-year literature review. Journal of Neurosurgery: Spine 100(3):254-267, 2004 41. Meyerson BA: Electric stimulation of the spinal cord and brain, in Bonica JJ, Loeser JD, Chapman CR (eds): The Management of Pain, ed. 2, Philadelphia: Lea& Febiger, Vol II, 1990, pp 1862-1877 42. Mullett KR, Rise MT, Shatin D: Design and function of spinal cord stimulators. Pain Digest 1:281-287, 1992 43. Andersen C: Complications in spinal cord stimulation for treatment of angina pectoris. Differences in unipolar and multipolar percutaneous inserted electrodes. Acta Cardiol 52:325-333, 1997 44. Hunt SM, McEwen J, McKenna SP: Measuring health status. London: Crom Helm, 1986 45. Ten Vaarwerk IAM, Jessurun GAJ, De Jongste MJL, Andersen C, et al: Clinical outcome of patients treated with spinal cord stimulation for therapeutically refractory angina pectoris. Heart 82(1):82-88, 1999 46. De Jongste M: Clinical trials with spinal cord and transcutaneous electrical nerve stimulation. Eur Heart J(Abstr Suppl) 21:128, 2000 47. Bagger J, Jensen B, Johannsen G: Long-term outcome of spinal cord electrical stimulation in patients with refractory chest pain. Clin Cardiol 21:286-288, 1998 48. Hautvast RW, De Jongste MJ, Staal MJ: Spinal cord stimulation in chronic intractable angina pectoris: a randomized, controlled efficacy study. Am Heart J 136:1114-1120, 1998 49. Mannheimer C, Eliasson T, Augustinsson L: Electrical stimulation versus coronary artery bypass surgery in severe angina pectoris: the ESBY study. Circulation 97:1157-1163, 1998 50. Vulink NCC, Overgaauw DM, Jessurun GAJ: The effects of spinal cord stimulation on quality of life in patients with therapeutically chronic refractory angina pectoris. Neuromodulation 2:33-40, 1999 51. De Jongste MJL: Defining the problem of intractable angina [resumen]. In: Barolat G, Stantonhicks M (eds.) Abstract Book of the Third International Congress of the International Neuromodulation Society and First Scientific Meeting of the American Neuromodulation Society. Orlando. Florida. Filadelfia: Thomas Jefferson University Press, 1996; 44 52. Jessurum GAJ, Ten Vaarwerk Inge AM, De Jongste MJL, Tio RA, Staal MJ: Sequelae of spinal cord stimulation for refractory angina
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53.
54.
55.
56.
57.
58.
59. 60.
61.
62.
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pectoris. Reliability and safety profile of long-term clinical application. Coron Artery Dis 8:33-38, 1997 Emond M, Mock MB, Davis KB, Fisher LD, Holmes DR, Chaitman BR et al: Long- term survival of medically treated patients in the Coronary Artery Surgery Study (CASS) Registry. Circulation 90: 2645-2657, 1994 Cameron AAC, Davis KB, Rogers WJ: Recurrence of angina after coronary artery bypass surgery: predictors and prognosis (CASS registry). J Am Coll Cardiol 26:895-899, 1995 Holmes DR, Davis K, Gersh BJ, et al: Risk factor profiles of patients with sudden cardiac death and death from other cardiac causes: a report from the Coronary Artery Surgery Study (CASS). J Am Coll Cardiol 13:524-530, 1989 Cupples LA, D’Agostino RB: Survival following initial cardiovascular events: 36-year follow-up. Framingham Heart Study, section 35. In: Kannel WB, Wolf PA, Garrison RJ, eds. The Framingham study: an epidemiological investigation of cardiovascular disease. NIH publication No 88 2969. Bethesda: National Heart, Lung, and Blood Institute, 1988 Lauer MS, Lytle B, Pashkow F, et al: Prediction of death and myocardial infarction by screening with exercise-thallium testing after coronary artery bypass grafting. Lancet 351:615-622, 1998 Mannheimer C, Eliasson T, Augustinsson L: Electrical stimulation versus coronary artery bypass surgery in severe angina pectoris: the ESBY study. Circulation 97:1157-1163, 1998 Murphy DF, Giles KE: Dorsal column stimulation for pain relief from intractable angina pectoris. Pain 28:365-368, 1987 Andersen C, Hole P, Oxhoj H: Does pain relief with spinal cord stimulation for angina conceal myocardial infarction? Br Heart J 71: 419-421, 1994 Hautvast R, De Jongste M, Staal M, van Gilst W, Lie K: Spinal cord stimulation in chronic intractable angina pectoris. A randomized, controlled efficacy study. Am Heart J 136:1114-1120, 1998 Mannheimer C, Eliasson T, Augustinsson L-E, et al: Electrical stimulation versus coronary artery bypass surgery in severe angina pectoris: the ESBY study. Circulation 97:1157-1163, 1998 Ekre O, Norrsell H, Währborg P, Eliasson T, Mannheimer C: Spinal cord stimulation and coronary artery bypass grafting provide equal improvement in quality of life— data from the ESBY Study (Abstr). Circulation 2000;Suppl(October 31)
Medullary neurostimulation in refractory angina X. Garcia-Moll, MD, R. Serra, MD From the Department of Cardiology and Anaesthesiology, Recovery and Pain Treatment, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain. KEYWORDS: Refractory angina; Ischemic heart disease; Spinal cord stimulation; Chronic pain
A growing number of patients present a clinical picture of refractory angina despite major advances in the pharmacological treatment of angina pectoris and myocardial reperfusion techniques. According to the European Society of Cardiology guidelines, refractory angina is a chronic pathology characterized by myocardial ischemia due to coronary artery disease that cannot be controlled by a combination of maximum tolerated drug treatment, angioplasty, and coronary revascularization surgery. To determine that a patient is not a candidate for revascularization, it has to be ruled out on the basis of a recent coronary angiogram, and the patient must be receiving the maximum tolerated doses of medical treatment. There must also be proof of reversible ischemia, and other non-coronary causes of chest pain must be ruled out. If all of the above does not resolve, then angina transcutaneous electrical nerve stimulation (TENS) or medullary electricostimulation (MES) should be considered. There are basically two mechanisms responsible for this clinical improvement: modification (not eradication) of pain perception, and its anti-ischemic properties in the myocardium. In this review, we describe our experience and we discuss the long-term symptomatic improvement and lower the functional category obtained with TENS or MES in patients with refractory angina. © 2006 Elsevier Inc. All rights reserved.
The past 15 years have seen major advances in the pharmacological treatment of angina pectoris and myocardial reperfusion techniques (angioplasty and surgery). Nonetheless, a growing number of patients present a clinical picture of refractory angina. According to the European Society of Cardiology guidelines, refractory angina is a chronic pathology characterized by myocardial ischemia due to coronary artery disease that cannot be controlled by a combination of maximum tolerated drug treatment, angioplasty, and coronary revascularization surgery. To confirm the diagnosis, it is necessary to demonstrate that reversible myocardial ischemia is the cause of the symptoms. Duration of more than 3 months is defined as chronic.1 To determine that a patient is not a candidate for revascularization, clinical cardiologists, interventional cardiologists, and heart surgeons must rule out the possibility of revascularization on the basis of a recent coronary angiogram, and the patient must be receiving the maximum tolerated doses of medical treatment. There must also be proof of reversible ischemia, and other noncoronary causes of Address reprint requests and correspondence: R. Serra, MD, Department of Anaesthesiology, Recovery and Pain Treatment, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain. E-mail address: [email protected]. 1084-208X/$ -see front matter © 2006 Elsevier Inc. All rights reserved. doi:10.1053/j.trap.2006.02.005
chest pain must be ruled out. Finally, information on the patient’s psychosocial situation is essential, as this may be an important cause of symptoms. There are no reliable data on the prevalence or incidence of refractory angina. The only data available are those extrapolated from coronary angiography records (5-15% of coronary angiography results are considered nonrevascularizable), or taken from data on chronic angina. About 5% to 10% of patients with unstable angina have a myocardial infarction or refractory angina in the hospital,2 and it is therefore likely that the number of patients with refractory angina will rise. A Spanish review of stable angina showed a prevalence of approximately 7.5% in people between the ages of 45 and 74,3 and it is thought that the figures are higher in northern Europe. In summary, we can say that the incidence in absolute numbers is 30,000 to 50,000 patients per year in Europe.
Determining suitable medical treatment for refractory angina The first step is to study the patient’s medical treatment because it is common that not all patients referred for
Garcia-Moll and Serra Table 1
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Diagnosis
I. Requires assessment by cardiologists and heart surgeons to ensure that the symptoms are of ischemic origin and that revascularisation is not possible. It is advisable to perform coronary angiography to exclude any new lesions that may call for intervention. II. Determine the presence of reversible myocardial ischemia when the decision is taken. III. The outpatient visit should include a review of pain history, physical examination and analysis of the patient’s medical treatment. We must ensure that the patient does not respond to the maximum tolerable treatment. We must also bear in mind the possibility of poor compliance with therapy, and explain the importance of complying fully with the treatment. IV. Exclude non-cardiac causes such as costochondritis, intercostal neuralgia, anaemia, thyrotoxicosis, reflux esophagitis. V. Multidisciplinary pain management, which can be based on psychological assessment methods such as hospital anxiety and depression scores. It should be determined whether psychotherapy may be beneficial since anxiety and depression are usually major pain components. The HADS questionnaire (Hospital Anxiety and Depression Score) is a simple screening tool to help identify patients who can benefit from a psychiatric or psychological study. VI. Rehabilitation program including secondary prevention by actively managing risk factors, physical reactivation, stress management and psychological support.
refractory angina are truly refractory to treatment. It is possible to increase the dose or try new drug combinations, and more aggressive treatment can improve symptoms in 45% to 83% of patients.4,5 Our diagnosis and treatment algorithm is described in Table 1, and is an adaptation of the algorithm recommended by the European Society of Cardiology.6,7 All patients should undergo antiaggregation and/or anticoagulation treatment in the absence of contraindications. Beta-blocker doses should be increased until a basal heart rate between 55 and 60 beats per minute is reached. The combination of beta-blockers with long-half-life calcium antagonists may provide significant improvement. The time of drug administration is also relevant. Patients with predominantly nocturnal angina should receive more medication at that time of day, whereas patients with exertion angina should get them in the morning. Given the circadian predominance of early-morning pain, we should consider administering topical nitroglycerin at night to cover the early morning hours. Nitrates may be limited because of tolerance. Other options may include molsidomine or nicorandil instead of nitrites during the period without topical nitrates. Amiodarone also has antiangina properties, although the evidence is limited. Obviously, aggravating factors like anemia, atrial fibrillation with rapid ventricular response, hypertension, or thyroid dysfunction must be corrected. We must not overlook the aggressive management of high cholesterol levels, which may provide long-term ben-
17 efits. The reduction of LDL cholesterol improves endothelial function in conductance vessels. An aspect of treatment that is often overlooked is cardiac rehabilitation. The functional limitation caused by refractory angina is usually considerable and may hamper patients so they cannot perform normal daily activities, causing them to feel socially isolated and incapable of physical activity, as they become increasingly dependent on their milieu. Although there are no guidelines on cardiac rehabilitation for patients with refractory angina, it is advisable to set up a rehabilitation program with these patients to reactivate them physically,8-12 help them stop smoking, lose excess weight, and change sedentary habits. Physical activity and a physically active life reduce cardiac mortality,13 prevent the development of atherosclerotic plaque,14 and improve myocardial perfusion.15 The program should be tailored to each patient’s needs. The patient should be informed about the use of prophylactic nitroglycerin before physical exercise and understand the importance of warm-up and cooling-off periods before and after exercise. If all of the above does not resolve the angina, other therapeutic options should be considered, such as transcutaneous electrical nerve stimulation (TENS) or medullary electrostimulation (MES). Opioids can be used in cases of refractory angina when other treatments fail. It is important to follow the opioid treatment guidelines for nonmalignant chronic pain and select patients adequately since the risk of addiction is low in socially well-adapted people with no history of drug abuse. Refractory angina is a pathology that seriously affects the quality of life and will probably increase in magnitude. Fortunately, we now have alternative treatments available, one of which is medullary electrostimulation (MES).
Medullary electrostimulation Electrical stimulation via electrodes as a treatment for intractable chronic pain began in 1967.16 Since then, MES has been used for many types of pain: tumors, lesions of the brachial plexus, phantom limb pain, angina pectoris, multiple sclerosis, peripheral vascular disease, arachnoiditis, etc. Early in the 1980s, Mannheimer and coworkers began treating angina pain with transcutaneous electrical nerve stimulation (TENS), and in 1987, Murphy and coworkers published the first results on the use of MES.17,18 Today its beneficial effect on the quality of life,19-21 by cutting down on angina episodes and enhancing functional capacity,22,23 has been amply demonstrated. There are basically two mechanisms responsible for this clinical improvement: modification (not eradication) of pain perception (the stimulation of spinal cord fibers that do not transmit pain to the brain lessens the impulses from fibers that do transmit it),24 and its antiischemic properties in the myocardium,25-31 although its mechanism of action is still a subject of controversy. The mechanisms suggested are a direct antiischemic effect due to diminished oxygen consumption in the myocardium or a redistribution of coronary
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Table 2 Clinical characteristics of the 56 patients included in our series Males (n, %) Age (years) Duration of ischemic heart disease (years) Duration of angina (years) NYHA class Previous acute MI (n, %) Previous PTCA (n, %) Previous revascularization surgery (n, %) Number of vessels involved Patients with three vessels (n, %) LVEF (%) Patients with 40% LVEF (n, %) Number of angina episodes per week Number of NTG per week
41, 73.2% 65.0 ⫾ 8.1 10.4 ⫾ 5.4 8.5 ⫾ 5.1 3.7 ⫾ 0.5 43, 76.3% 19, 33.9% 42, 75% 2.8 ⫾ 0.6 42, 75% 47.7 ⫾ 16.2 22, 39% 7.7 ⫾ 3.4 6.6 ⫾ 3.8
flow.17,31-34 This effect could be explained by the reduction of sympathetic tone or by a change in the cardiac metabolism of beta-endorphin.35-37 The antiischemic effect has been demonstrated in studies with 24-hour Holter ambulatory ECG recordings and exercise tests in which it has been shown that depression of the ST segment, indicative of the presence of myocardial ischemia, is reduced under medullary stimulation.19,22,23 Furthermore, the onset of angina is delayed.32 However, there is controversy over whether myocardial perfusion is increased during maximum exercise. Some studies show that myocardial perfusion improves in ischemic areas, with concomitant alteration of the coronary flow reserve as assessed by positron emission tomography.38 The difference in results could be explained by the different experimental methods. There is currently no doubt that MES does not have an anesthetic effect, which means that the patient will feel pain with a major angina episode or a myocardial infarction.39 This is one of the main reasons for reticence within the cardiology community: the safety of MES. It is felt that if the reduced angina is due exclusively to an anesthetic effect on pain sensitivity, the patient will continue to experience the same ischemic episodes, completely silent because of the electrostimulation, with the consequent danger resulting from eliminating the alarm signal, which is the angina pain. However, it has been shown that patients retain the ability to feel ischemic pain.
Medullary electrostimulation: our experience Our series consisted of 56 patients (from 1 February 1993 to 31 August 2005) treated for refractory angina with MES. Their clinical profiles are shown in Table 2. All of them met the following inclusion criteria: (a) severe exertion angina (class III-IV) or subacute unstable angina, released from the coronary care unit but with continued episodes preventing their release from hospital; (b) angina resistant to maximum tolerated drug treatment, despite good compliance, over a period of at least 1 month; (c) severe lesions (⬎70%) in the coronary arteries, demonstrated by coronary angiography; (d) reversible myocardial ischemia documented by challenge testing or ECG record-
ing during a pain episode; (e) technical impossibility of myocardial reperfusion (surgery or coronary angioplasty [PTCA]) or very high-risk surgical indication; (f) reasonable certainty that pain episodes were mainly of ischemic origin (chest pain episodes described by the patient as identical to those felt in our presence with electrocardiographic changes, which remitted or improved with sublingual nitroglycerin [s.l. NTG]); (g) absence of correctible aggravating factors; and (h) informed consent.
Implantation of electrostimulator, possible complications, and follow-up Before performing the procedure, we checked compliance with the inclusion criteria and suspended the administration of antiaggregants 10 days before implantation. If the patient was under treatment with dicumarinics, we switched to heparin beforehand. One hour before the procedure we administered an antibiotic (cefazolin). The entire system was implanted in a single operation in two stages. In the first stage of the procedure, we placed the electrode under fluoroscopic control with the patient in prone decubitus (Figure 1). We found it useful to place a few paper clips in the skin to locate the area where we wanted to insert the electrode tip and to ensure that the patient was in an anteroposterior position (Figure 2). Once the patient was positioned and with maximum sterility guaranteed, we started the procedure under local anesthesia at T4 –T5 to locate the epidural space and insert the electrode percutaneously. Under fluoroscopic control, it was placed in the C7–T2 epidural space so that it would cause paresthesia in the region where the angina pain irradiated. With the electrode in place, we tunnelled through the rest of the right side and closed the skin provisionally (Figure 3). With this maneuver we could ensure that there were no kinks in the electrode, keep the extension wire area as small as possible, and minimize patient discomfort. We then went to a second surgical stage with the patient in lateral decubitus to place the extension wire and the impulse generator in a subcutaneous pouch, usually in the right subcostal area (in right-handed patients), making it easier for the patient to operate the controls. The complications related to MES may be technical or biological.40 The technical complications most often reported in the literature are breakage or displacement of the electrodes, depleted batteries, or generator failure.41,42 Migration of the electrode has been described in 23% of cases,43 especially with unipolar electrodes (up to 45%). In our experience, this percentage was considerably lower— around 10%. The biological complications most often described are infection of the system (2% in our experience), loss of cerebrospinal fluid, pain at the site of the incision, electrode or generator,41 epidural bleeding, seroma, hematoma, paralysis, over- or under-stimulation, allergic reaction, etc. Clinical controls were performed by the clinical cardiologist and the implanting anesthesiologist 1 month after implantation of the system and every 4 to 6 months thereafter (depending on the patient’s stability). The following items were monitored during follow-up: weekly sublingual
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Figure 1
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First stage of system implantation. Prone decubitus. (Color version of figure appears online.)
NTG consumption, number of weekly angina episodes, death from cardiac causes, death from noncardiac causes, cardiovascular clinical events requiring hospitalization (acute myocardial infarction [acute MI], unstable angina, heart failure, stroke), and complications inherent in the procedure itself (displacement or breakage of the electrodes, infection, extrusion of the battery, etc.).
The patients were also assessed with the Nottingham Health Profile44 before the procedure, 1 month after, and thereafter every year. This test includes seven parameters: physical mobility, sleep, energy, social isolation, emotional reactions, pain, and overall assessment.
Results of our experience
Figure 2
Final electrode position.
The European series, the largest published up to now (n ⫽ 517 patients),45 had a mean follow-up of 23 months (0-128) for the entire patient group, 23 months (0-128) for the survivors, and 19 months (0-122) for patients who died. The follow-up in our series was considerably longer: 49.0 ⫾ 34.6 months for the total, 61.0 ⫾ 38.4 months for survivors, and 36.1 ⫾ 25.1 months for those who died (P ⫽ 0.001). The causes of death in the European series were cardiac in 51%, noncardiac in 24%, and unknown in 25%, whereas in our group, they were 65%, 17%, and 17%, respectively. It was estimated that the mortality rate in the former group of patients was 3.5% to 5% per year, lower than that found in our series and probably due to the substantial difference in follow-up (in our experience the mortality rate was lower in the first few years and increased as the follow-up lengthened). The left ventricular ejection fraction was a relevant variable in patient prognosis. Patients with LVEF ⬍ 40% had a higher mortality rate than those with LVEF ⬎ 40%. The functional class improved significantly after MES implantation. The basal overall and pain scores recorded by the Nottingham profile improved significantly after the first month (basal pain: 62.0 [50.0-75.0]; pain at 1 month: 25.0 [12.041.0]; P ⬍ 0.001; basal overall: 71.0 [43.0-85.0]; overall at 1 month: 28.0 [14.0-57.0]; P ⬍ 0.001). The Nottingham profile administered at the end of 1 year did not show significant differences as compared with the scores 1 month
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Figure 3
Second stage of system implantation. Lateral decubitus. (Color version of figure appears online.)
after implantation, suggesting that the beneficial effect is sustained over time (pain: 25.5 [12.5-52.3]; overall: 33.0 [14.0-57.0]). During the follow-up, 23 patients (56.1%) had no cardiovascular complications that required hospitalization; the remaining 18 patients (43.9%) recorded a total of 29 admissions. The most common complication found during follow-up was unstable angina, followed by acute myocardial infarction, heart failure, and stroke. Twenty-four patients died (5 from fatal MI, 5 from heart failure, 2 of stroke, and 6 from sudden death—1 from cancer, 1 from pneumonia, and 4 of undetermined causes). Consequently, the overall yearly mortality rate was 9.7% and 7.7% for cardiac causes. The
Figure 4
only technical complications we recorded were a case of immediate postimplantation infection that required the removal of the entire implant and placement of a new system 3 months later, and a case of extrusion of the extension wire 6 months after implantation, which was resolved by removal and placement of a new wire which has now been functioning correctly for 45 months. Finally, we had a case of electrical cellulites at the level of the IPG-implantable generator pocket programmed in unipolar mode in a patient 5 years after treatment, which was resolved by switching to bipolar mode (Figure 4). We had no cases of electrode breakage or displacement. We took chest and cervical (AP and lateral) X-rays to ensure the correct position of the electrode in the posterior
Electrical cellulitis secondary to unipolar stimulation. (Color version of figure appears online.)
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epidural space. Patients followed a stimulation schedule of 1 hour every 8 hours.
Discussion MES systems have been implanted in approximately 2000 patients worldwide.46 The long-term follow-up studies show that symptoms improve in approximately 80% of patients.47 This improvement depends on appropriate patient selection and careful monitoring in care units specialized in this type of treatment. With MES there has been a significant reduction in the number of angina episodes and nitrate consumption, even in the long term, with improvement in functional class and significant reduction in the number of hospital admissions.27,28,39,43,47-50 In our experience, MES has drastically lowered the number of admissions per patient per year (2.3 as compared with 0.28).39 Hospital visits were twice higher in the group of deceased patients when compared with the group of living patients (0.37 as compared with 0.19). However, in the deceased group, the number of admissions was drastically reduced in relation to the pretreatment rate (2.03 as compared with 0.37). This reduction may contribute to improve quality of life while reducing health costs. The enhanced quality of life was also reflected in the significant improvement in the Nottingham profile indices in the short and long term within the population studied. In our series, cardiovascular events represented the main cause of mortality with 7.7% of the cases per year of the total 9.7% per year. These figures are similar to those in the only two studies, both retrospective, that have provided information to date on morbidity and mortality in patients treated with electrostimulation. The European retrospective multicenter study51 mentions only the overall mortality, which was 8% per year, and in the historical cohort study by De Jongste52 with 57 patients monitored for an average of 23 months, the mortality rate was 6.5%. A study with mortality figures in patient groups with a comparable profile but without MES treatment is the Coronary Artery Surgery Study (CASS)53-55 and the Framingham cohort.56,57 In this North American study, cardiac mortality in patients with three vessels involved was 32% over 4 years and increased to 50% in the subgroup with a left ventricular ejection fraction below 35%. Therefore, the mortality found in our series of patients treated with MES was not greater than expected in patients with a similar clinical profile, as shown in the ESBY study,58 which suggests that neuromodulation is as effective as coronary revascularization, in reducing anginal episodes and mortality. Other studies have provide additional data to rule out the concern that MES causes higher mortality.27,59,60
21 A retrospective study showed that MES has no negative influence on mortality or morbidity as compared with matched groups,45 which is similar to the findings in our prospective series as compared with data taken from the literature on patients with similar characteristics without MES treatment.39 Indeed, the ESBY study showed that patients who are candidates for revascularization surgery with higher surgical risk randomized to MES had less mortality (but a higher rate of readmissions for angina) than patients randomized to revascularization surgery.62 Both groups showed significantly fewer angina episodes and reduced sublingual nitroglycerin intake, with no difference between them. The effects were sustained at 5 years.63 In our series, we assessed the mortality-predicting parameters (yes/no) by logistic regression and identified the following independent variables associated with mortality: ejection fraction of 40% or less (in accordance with data currently available on the relevance of this parameter as a prognostic factor in ischemic heart disease) and sex. In our series, men had a lower mortality rate than women, even after adjusting for the ejection fraction and years of ischemic heart disease. A third parameter that tended to be associated with mortality was the previous duration of ischemic heart disease, probably because this variable encompasses others, such as the number of prior infarctions or prior revascularization. On the other hand, as opposed to the European series, diabetes and the absence of beta-blockers in treatment had no independent predictive value in our series. Another item worthy of mention is the low incidence of technical complications like electrode breakage or displacement. This is common to all the series published after tetrapolar electrodes came into use, doing away with the large number of problems found in earlier studies. An additional advantage of MES is that it is a treatment system that can be removed, as opposed to ablation surgery. Moreover, MES has no long-term side effects, as compared with the major systemic side effects of opioids. In our series, we looked specifically at the follow-up of unstable angina cases in the subacute stage, which is an indication that has been much discussed up to now. The mortality rate in this group of patients was higher but not statistically significant. Morbidity was similar and the improvement in quality of life was greater. This is not surprising since, if we compare the clinical profiles of both groups of patients, we note that they are very much alike. Actually, they are the same type of patients, with numerous hospital admissions at two different moments in their disease progression—some during the outpatient period after being released from hospital, and others while in hospital, following the acute phase in the coronary care unit. Finally, our data confirm the hypothesis that refractory unstable angina in the subacute phase is a valid indication for MES treatment.
Clinical efficacy studies TENS and MES have been shown to provide long-term symptomatic improvement and lower the functional category as established by the Canadian Cardiovascular Society, enhancing the possibilities for everyday social activities and reducing the intake of sublingual nitroglycerin.61
Conclusion MES is a valid technique safe in the long term for treating patients with refractory angina, since it reduces morbidity,
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does not increase mortality, and has a low incidence of technical complications. MES can therefore be considered a safe and effective therapeutic alternative for this type of patients, in both the stable and subacute unstable phases. Its lasting long-term beneficial effects can also have a positive impact on economic and social costs by cutting down on the number of patient days in hospital.
References 1. Mannheimer C, Camici P, Chester MR, Collins A, DeJongste M, Eliasson T, Follath F, Hellemans I, Herlitz J, Lüscher T, Pasic M, Thelle D: The problem of chronic refractory angina: Report from the ESC Joint Study Group on the Treatment of Refractory Angina. Eur Heart J 23(5):355-370, 2002 2. Yusuf S: Design, baseline characteristics, and preliminary clinical results of the Organization to Assess Strategies for Ischemic Syndromes-2 (OASIS-2) trial. Am J Cardiol 1999;84(5A):20M–25 3. Cosín J, Asín E, Marrugat J, et al: Prevalence of angina pectoris in Spain. PANES Study group. Eur J Epidemiol 4:323-330, 1999 4. Ruck A, Drvota V, KastrupJ, DudekD, Boetker HE, Ruzyllo W, Glogar D, Sylvén C: On behalf: the EUROINJECT ONE investigators. How refractory is refractory angina? A three-year follow up of 225 patients. Abstract 3853. European Society of Cardiology Congress 2005. Stockholm September 3rd-7th 2005 5. Nägele H, Kalmar P, Labeck M, et al: Transmyokardiale Laserrevaskularisation —Behandlungsoption bei der koronaren Herzerkrankung. Z Kardiol 86:171-178, 1997 6. Chester M: Draft guidelines for the management of refractory angina on behalf of the UK Refractory Angina Group. Eur Heart J 1999; 20(Abstr Suppl):479 7. Eliasson T: Therapeutic options in severe angina pectoris and endstage coronary artery disease. In: XXth Congress of the European Society of Cardiology; 1998 8. WHO: The rehabilitation of patients with cardiovascular diseases. Report on a seminar. EURO 0381. Copenhagen, 1969: WHO, regional office for Europe; 1969 9. Second Joint Task Force of European and other Societies on Coronary Prevention. Prevention of coronary heart disease in clinical practice. Eur Heart J 19:1434-1503, 1998 10. Working group on Rehabilitation of the European Society of Cardiology. Long-term comprehensive care of cardiac patients. Eur Heart J 1992;13 (Suppl C) 11. Smith S, Blair S, Crique M, et al: American Heart Association Consensus statement: Prevention of heart attack and death in patients with coronary artery disease. Circulation 92:2-4, 1995 12. Wenger N. Froelicher E. Smith L. el at: Clinical Practice Guideline: Cardiac Rehabilitation. U.S. Department of Health and Human Services. AHCPR publication 13. O’Connor G, Buring J, Yusuf S, et al: An overview of randomized trials of rehabilitation with exercise after myocardial infarction. Circulation 80:234-244, 1989 14. Niebauer J, Hambrecht R, Velich T, et al: Attenuated progression of coronary artery disease after 6 years of multifactorial risk intervention. Circulation 96:2534-2541, 1997 15. Linxue L, Nohara R, Makita S, et al: Effect of long-term exercise training on regional myocardial perfusion changes in patients with coronary artery disease. Jpn Circ J 63:73-78, 1999 16. Shealy S, Mortimer JT, Reswick JB: Electrical inhibition of pain by stimulation of the dorsal columns: preliminary clinical report. Anesth Analg 46:489-491, 1967 17. Mannheimer C, Carlson CA, Emanuelsson H, Vedin A, Vaagstein F, Wilhelmsson C: The effects of transcutaneous electrical nerve stimulation in patients with severe angina pectoris. Circulation 71:308-316, 1985 18. Murphy DF, Giles KE: Dorsal column stimulation for pain relief from intractable angina pectoris. Pain 28:365-368, 1987
19. De Jongste MJL, Hautvast RWM, Hillege JL, Lie KI on behalf of the Working Group on Neurocardiology. Efficacy of spinal cord stimulation as adjuvant therapy for intractable angina pectoris. J Am Coll Cardiol 23:1592-1597, 1994 20. García Moll M, García-Moll X, Serra R: Tratamiento de la angina refractaria con electroestimulación medular: impacto sobre la calidad de vida [resumen]. Rev Esp Cardiol 50(Supl 6):370, 1997 21. González-Darder JM, Vázquez JL, Canela P, González-Martínez V: Calidad de vida en el paciente con angina inestable tratado con estimulación eléctrica medular. Med Clin (Barc) 95:768-770, 1990 22. Sanderson JE, Brooksby P, Waterhouse D, Palmer RGB, Neubauer K: Epidural spinal electrical stimulation for severe angina: a study of its effect on symptoms, exercice tolerance and degree of ischemia. Eur Heart J 13:628-633, 1992 23. Mannheimer C, Augustinsson LE, Carlsson CA, Manhem K, Wilhelmsson C: Epidural spinal electrical stimulation in severe angina pectoris. Br Heart J 59:56-61, 1988 24. Melzack R, Wall PD: Pain mechanisms: a new theory. Science 150: 971-979, 1965 25. González-Darder JM, González-Martínez V, Canela P, Hernández R: Estimulación eléctrica medular en la angina rebelde e incapacitante. Protocolo y resultado a largo plazo. Neurocirugía 4:305-311, 1993 26. De Jongste MJL, Haaaksma J, Hautvast RWM, Hillege HL, Meyler JW, Staal MJ et al: Effects of spinal cord stimulation on myocardial ischemia during day life in patients with severe coronary artery disease. A prospective ambulatory electrocardiographic study. Br Heart J 71:413-418, 1994 27. Sanderson JE, Ibrahim B, Waterhouse D, Palmer RBG: Spinal electrical stimulation for intractable angina; long-term clinical outcome and safety. Eur Heart J 15:810-814, 1994 28. Elliasson T, Fern S, Augustinsson LE, Mannheimer C: Safety aspects of spinal cord stimulation in severe angina pectoris. Coron Artery Dis 5:845-850, 1994 29. Hautvast RWM: Spinal cord stimulation for chronic refractory angina pectoris; an investigation of its efficacy, mechanism and neuronal pathways [tesis doctoral]. Groningen, Holanda: University of Groningen, 127-139, 1997 30. Kujacic V, Eliasson T, Mannheimer C, Jablonskiene D, Augustinsson LE, Emanuelsson H: Assessment of the influence of spinal cord stimulation on left ventricular function in patients with severe angina pectoris: an echocardiographic study. Eur Heart J 14:1238-1244, 1993 31. Mannheimer C, Eliasson T, Andersson B, Bergh CH, Augustinsson LE, Emanuelsson H: Effects of spinal cord stimulation in angina pectoris induced by pacing and possible mechanisms of action. BMJ 307:477-480, 1993 32. De Landsherre C, Mannheimer C, Habets A, et al: Effect of spinal cord stimulation on regional myocardial perfusion assessed by positron emission tomugraphy. Am J Cardiol 69:1143-1149, 1992 33. Hautvast R, De Jongste M, Blanksma P, et al: Spinal cord stimulation causes redistribution in myocardial perfusion during dipramidole stresss testing in patients with refractory angina pectoris as assessed by 13 NH3-positron emission tomography. Am J Cardiol 77:462-467, 1996 34. Mobilia G, Zuin G, Zanco P, et al: Effects of spinal cord stimulation on regional myocardial blood flow in patients with refractory angina. A positron emission tomography study. (In italian). G Ital Cardiol 28:1113-1119, 1998 35. Norrsell H, Eliasson T, Mannheimer C, et al: Effects of pacinginduced myocardial stress and spinal cord stimulation on whole body and cardiac norepinephrine spillover. Eur Heart J 18:1890-1896, 1997 36. Emanuelsson H, Mannheimer C, Waagstein F, Wilhelmsson C: Catecholamine metabolism during pacing-induced angina pectoris and the effect of transcutaneous electrical nerve stimulation. Am Heart J 114: 1360-1366, 1987 37. Eliasson T, Mannheimer C, Waagstein F, et al: Myocardial turnover of endogenous opioids and calcitonin gene-related peptide in the human heart and the effects of spinal cord stimulation on pacing-induced angina pectoris. Cardiology 89:170-177, 1998 38. Hautvast RW, Blanksma PK, De Jongste MJ, Pruim J, van der Wall EE, Vaalburg W, Lie KI: Effect of spinal cord stimulation on myocardial blood flow assessed by positron emission tomography in patients with refractory angina pectoris. Am J Cardiol 77(7):462-467, 1996
Garcia-Moll and Serra
Medullary Neurostimulation
39. Garcia-Moll M, Serra R, Garcia-Moll X: Refractory angina treated by spinal cord stimulation. The results of a long-term follow-up. Rev Esp Cardiol 53(3):321-326, 2000 40. Cameron T: Safety and efficacy of spinal cord stimulation for the treatment of chronic pain: a 20-year literature review. Journal of Neurosurgery: Spine 100(3):254-267, 2004 41. Meyerson BA: Electric stimulation of the spinal cord and brain, in Bonica JJ, Loeser JD, Chapman CR (eds): The Management of Pain, ed. 2, Philadelphia: Lea& Febiger, Vol II, 1990, pp 1862-1877 42. Mullett KR, Rise MT, Shatin D: Design and function of spinal cord stimulators. Pain Digest 1:281-287, 1992 43. Andersen C: Complications in spinal cord stimulation for treatment of angina pectoris. Differences in unipolar and multipolar percutaneous inserted electrodes. Acta Cardiol 52:325-333, 1997 44. Hunt SM, McEwen J, McKenna SP: Measuring health status. London: Crom Helm, 1986 45. Ten Vaarwerk IAM, Jessurun GAJ, De Jongste MJL, Andersen C, et al: Clinical outcome of patients treated with spinal cord stimulation for therapeutically refractory angina pectoris. Heart 82(1):82-88, 1999 46. De Jongste M: Clinical trials with spinal cord and transcutaneous electrical nerve stimulation. Eur Heart J(Abstr Suppl) 21:128, 2000 47. Bagger J, Jensen B, Johannsen G: Long-term outcome of spinal cord electrical stimulation in patients with refractory chest pain. Clin Cardiol 21:286-288, 1998 48. Hautvast RW, De Jongste MJ, Staal MJ: Spinal cord stimulation in chronic intractable angina pectoris: a randomized, controlled efficacy study. Am Heart J 136:1114-1120, 1998 49. Mannheimer C, Eliasson T, Augustinsson L: Electrical stimulation versus coronary artery bypass surgery in severe angina pectoris: the ESBY study. Circulation 97:1157-1163, 1998 50. Vulink NCC, Overgaauw DM, Jessurun GAJ: The effects of spinal cord stimulation on quality of life in patients with therapeutically chronic refractory angina pectoris. Neuromodulation 2:33-40, 1999 51. De Jongste MJL: Defining the problem of intractable angina [resumen]. In: Barolat G, Stantonhicks M (eds.) Abstract Book of the Third International Congress of the International Neuromodulation Society and First Scientific Meeting of the American Neuromodulation Society. Orlando. Florida. Filadelfia: Thomas Jefferson University Press, 1996; 44 52. Jessurum GAJ, Ten Vaarwerk Inge AM, De Jongste MJL, Tio RA, Staal MJ: Sequelae of spinal cord stimulation for refractory angina
23
53.
54.
55.
56.
57.
58.
59. 60.
61.
62.
63.
pectoris. Reliability and safety profile of long-term clinical application. Coron Artery Dis 8:33-38, 1997 Emond M, Mock MB, Davis KB, Fisher LD, Holmes DR, Chaitman BR et al: Long- term survival of medically treated patients in the Coronary Artery Surgery Study (CASS) Registry. Circulation 90: 2645-2657, 1994 Cameron AAC, Davis KB, Rogers WJ: Recurrence of angina after coronary artery bypass surgery: predictors and prognosis (CASS registry). J Am Coll Cardiol 26:895-899, 1995 Holmes DR, Davis K, Gersh BJ, et al: Risk factor profiles of patients with sudden cardiac death and death from other cardiac causes: a report from the Coronary Artery Surgery Study (CASS). J Am Coll Cardiol 13:524-530, 1989 Cupples LA, D’Agostino RB: Survival following initial cardiovascular events: 36-year follow-up. Framingham Heart Study, section 35. In: Kannel WB, Wolf PA, Garrison RJ, eds. The Framingham study: an epidemiological investigation of cardiovascular disease. NIH publication No 88 2969. Bethesda: National Heart, Lung, and Blood Institute, 1988 Lauer MS, Lytle B, Pashkow F, et al: Prediction of death and myocardial infarction by screening with exercise-thallium testing after coronary artery bypass grafting. Lancet 351:615-622, 1998 Mannheimer C, Eliasson T, Augustinsson L: Electrical stimulation versus coronary artery bypass surgery in severe angina pectoris: the ESBY study. Circulation 97:1157-1163, 1998 Murphy DF, Giles KE: Dorsal column stimulation for pain relief from intractable angina pectoris. Pain 28:365-368, 1987 Andersen C, Hole P, Oxhoj H: Does pain relief with spinal cord stimulation for angina conceal myocardial infarction? Br Heart J 71: 419-421, 1994 Hautvast R, De Jongste M, Staal M, van Gilst W, Lie K: Spinal cord stimulation in chronic intractable angina pectoris. A randomized, controlled efficacy study. Am Heart J 136:1114-1120, 1998 Mannheimer C, Eliasson T, Augustinsson L-E, et al: Electrical stimulation versus coronary artery bypass surgery in severe angina pectoris: the ESBY study. Circulation 97:1157-1163, 1998 Ekre O, Norrsell H, Währborg P, Eliasson T, Mannheimer C: Spinal cord stimulation and coronary artery bypass grafting provide equal improvement in quality of life— data from the ESBY Study (Abstr). Circulation 2000;Suppl(October 31)